Abstract 2045: Analysis of the matrisome in malignant gliomas reveals architectural heterogeneity of the tumor microenvironment and discloses a prognostic signature of extracellular matrix targets
Authors: Minhein Htet, Somanath Kundu, Abigail Venskus, Cynthia S. Weickert, Yasir Ahmed-Braimah, Mariano S. Viapiano
Journal: Cancer Research (2023)

Abstract Novel strategies against malignant gliomas are devoting increasing effort to disrupting the tumor microenvironment (TME), hoping to overcome the challenges posed by the genetic heterogeneity of the tumor cells. The tumor extracellular matrix (ECM) organizes the cytoarchitecture of the TME and presents highly accessible potential targets; strikingly, a systematic analysis of glioma ECM is still missing. To address this gap we performed bioinformatic analysis of the entire matrisome complement of glioblastoma (GBM) and low-grade gliomas (LGG), adding a set of surrogate genes to assess non-protein ECM components predominant in the brain, such as hyaluronic acid. We utilized RNAseq data from the GBM/LGG TCGA dataset (N=668 tumors) as well as our own collection of bulk-sequenced GBM (N=90) and GBM stem cells (N=45). We also supplemented TCGA normal brain data with high-depth sequencing from the subependymal zone of normal adult individuals (N=28), thus assessing the ECM of the putative niche of origin of GBM. Unsupervised K-medoid clustering revealed four GBM clusters defined by ECM differences, two of which superimposed well with classical and proneural classification of GBM. The other two clusters shared features of mesenchymal GBMs but were well differentiated by expression of fibrillar versus non-fibrillar collagens and MMP versus ADAM proteases, suggesting different phenotypes for ECM architecture and remodeling. Extension of this analysis to LGGs identified six well-defined, matrisome-dependent tumor clusters that were independent of histology, transcriptional subtypes, or IDH1 status. Age-adjusted multivariate Cox analysis revealed one particular GBM cluster with "neurodevelopmental-like" ECM having significantly extended overall survival. Using stringent filtering criteria to select ECM genes expressed in GBM we identified 93 candidate ECM genes consistently upregulated across all matrisome or transcriptional subtypes. Regional analysis of these genes allocated most of them to the microvascularized regions of the tumor, suggesting that the most significant ECM remodeling is associated with vascularization rather than tumor invasion. Ongoing scRNAseq analysis suggests that ECM remodeling genes are largely expressed by the tumor cells and tumor-associated astrocytes, with little contribution of myeloid cells, departing from what has been observed in other solid tumors. In sum, these results provide for the first time a comprehensive description of the heterogeneity of the glioma ECM and reveal both a prognostic signature and a number of attractive actionable targets exposed in the TME of these brain cancers. Citation Format: Minhein Htet, Somanath Kundu, Abigail Venskus, Cynthia S. Weickert, Yasir Ahmed-Braimah, Mariano S. Viapiano. Analysis of the matrisome in malignant gliomas reveals architectural heterogeneity of the tumor microenvironment and discloses a prognostic signature of extracellular matrix targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2045.